Transition to androgen-independence in prostate cancer

Navarro, Domingo; Luzardo, Octavio P.; Fernández, Leandro; Chesa, Nicolás; Díaz-Chico, B.N.

doi:10.1016/s0960-0760(02)00064-x

Cited by 85 publications

(83 citation statements)

References 40 publications

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“…AR hypersensitivity, promiscuity, amplification etc.) (57). In addition androgen-independent clones of LNCaP (LNCaP-abl and AI:LNCaP) have been developed which are associated with upregulated AR expression and higher levels of AR reporter gene activity, indicating preserved androgen pathway function (58).…”

Section: Statistical Analysesmentioning

confidence: 99%

DNA demethylation and histone deacetylation inhibition co‐operate to re‐express estrogen receptor beta and induce apoptosis in prostate cancer cell‐lines

et al. 2007

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tom@pelhamcourt.clara.co.uk Introduction Epigenetic silencing mechanisms are increasingly thought to play a major role in the development of human cancers, including prostate cancer. The two major epigenetic regulatory mechanisms involve alterations in DNA methylation and histone acetylation status. Promoter CpG island hypermethylation and histone hypoacetylation, catalysed by DNA methyltransferase (DNMT) and histone deacetylase (HDAC) respectively, are associated with transcriptional repression. Evidence in other cancers suggests the two mechanisms are dynamically linked, yet few studies have examined the potential interaction of the two pathways in prostate cancer. Here we report a synergistic, apoptotic effect of treatment with a demethylating agent and a histone deacetylase inhibitor on cultured prostate cancer cells, with associated re-expression of the putative antiproliferative agent oestrogen receptor beta.Methods LNCaP, DU-145 and PC-3 cells were pre-treated with the DNMT inhibitor 5'-aza-2'-deoxycytidine (5-AZAC) for 72 hours followed by 24 hours combined treatment with 5-AZAC and the HDAC inhibitor trichostatin A (TSA). Following treatment, cells were either processed for cell proliferation, cell toxicity, cell viability and apoptosis assays, or harvested for quantitative real-time RT-PCR gene expression analyses. Assessed target genes were oestrogen receptor beta (ERβ), androgen receptor (AR), progesterone receptor (PGR) and prostate specific antigen (PSA). ResultsIn all cell-lines co-treatment with 5-AZAC and TSA was associated with significantly reduced cell proliferation when compared with control groups (p<0.05); associated reduced cell viability and increased cell death was seen in all cases. Caspase activation was significantly increased in the co-treatment group, indicating that apoptosis was a major mechanism of cell death. Most marked effects were seen in the androgen-dependent, AR-positive LNCaP cell-line. In all cell-lines a marked synergistic re-expression of ERβ was identified in the co-treatment group, a finding which was not seen for either AR or PSA. A similar re-expression of PGR was also identified. ConclusionsAt concentrations associated with gene re-expression, the DNA demethylating agent 5-AZAC and the HDAC inhibitor TSA co-operate in an additive and synergistic way to induce apoptosis in prostate cancer cell-lines. Increased apoptosis in the co-treatment group was associated with marked re-expression of ERβ, which is an intriguing finding, raising the possibility of further targeting of prostate cancer cells with ERβ-selective agents such as phytooestrogens and selective oestrogen receptor modulators (SERMs).

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Section: Statistical Analysesmentioning

confidence: 99%

DNA demethylation and histone deacetylation inhibition co‐operate to re‐express estrogen receptor beta and induce apoptosis in prostate cancer cell‐lines

et al. 2007

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“…AR has been one of major focuses in studies of normal and abnormal prostate growth. 58,59 Although the general molecular mechanisms of androgen action have been established, the discovery of specific molecular pathways that lead to precise regulation of AR in either androgendependent or -independent manners is still a critical area of research in normal prostate function and in prostate cancer. Interestingly, two recent reports indicated that AR contains two Akt phosphorylation consensus sequences (RXRXXS/T), 9 located at S213 (RAREAS) and S791 (RMRHLS), and both were shown to be phosphorylated by Akt in vitro.…”

Section: The Role Of Akt In Signal Transductionmentioning

confidence: 99%

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

Ittmann

Ayala

et al. 2005

Prostate Cancer Prostatic Dis

110

112

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The PI3-K-Akt pathway plays a central role in the development and progression of prostate cancer and other malignancies. We review original studies and summarize relevant sections of previous reviews concerning the relationships between abnormalities in the PI3-K-Akt pathway and prostate cancer progression. We discuss laboratory and clinical data that indicate gene perturbation and dysregulation of PI3-K-Akt pathway is common in prostate cancer and other malignancies. We further discuss the critical role of the PI3-K-Akt pathway in the oncogenic signaling network and provide examples that establish the PI3-K-Akt pathway as a focal point for the future development of informative biomarkers and effective therapies for prostate cancer.

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“…Loss of androgen sensitivity is generally considered to have four causes: selection of cancer clones; adaptation of cells to an environment without androgen; an alternative pathway of signal transduction; and involvement of ARs (Grossmann et al 2001, Gelmann 2002, Navarro et al 2002. The present article focuses on AR involvement in the progression of androgen-responsive prostate cancer to being androgen-unresponsive.…”

Section: Loss Of Hormone Sensitivity In Prostate Cancermentioning

confidence: 99%

Androgen receptor involvement in the progression of prostate cancer.

Suzuki¹,

Ueda²,

Ichikawa³

et al. 2003

Endocrine-Related Cancer

154

116

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Since the growth of prostate cancer is androgen-sensitive, metastatic disease has been treated by hormonal therapy. Almost all prostate cancer patients initially respond to hormonal therapy, but the majority gradually develop resistance. The mechanism of the change in tumors from being androgen-responsive to androgen-unresponsive is generally explained by clonal selection, adaptation, an alternative pathway of signal transduction and androgen receptor (AR) involvement. Since androgen action is mediated by ARs, abnormalities in ARs are believed to play an important role in the progression of prostate cancer. Hyperactivated AR gene mutations have been detected in 20-30% of hormone-refractory tumors and functional analyses have demonstrated a wide responsiveness to estrogens, progesterone and anti-androgens as well as to androgens. The AR is highly amplified in 30% of patients with hormone-refractory prostate cancer that has been treated by castration without anti-androgens. Immunohistochemical studies of ARs in hormone-refractory prostate cancer specimens have shown that AR protein is down-regulated. DNA hypermethylation of the AR promoter region leading to AR down-regulation has been identified in 30% of hormone-refractory prostate cancers. The AR N-terminal domain in the LNCaP cell line model is activated by interleukin-6 via mitogen-activated protein kinase and single transducers and activators of transcription 3. Epidemiological observations have shown that short CAG repeats are more frequently associated with higher transactivational function in the African-American population, which may explain racial differences in the incidence of prostate cancer. Among Japanese, a short CAG repeat appears to predict a response to hormonal therapy, indicating a positive prognostic value and good prognosis at the metastatic stage of prostate cancer. Several co-factors between ARs and the transcriptional complex have been cloned and reports indicate that steroid receptor co-activator 1 is correlated with the hormone-refractory progression of prostate cancer.Thus, ARs plays an important role in the progression of prostate cancer. Based on the findings described above, genetic diagnosis and/or molecular-targeted therapy via AR pathways can be developed for hormone-refractory states.

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Transition to androgen-independence in prostate cancer

Cited by 85 publications

References 40 publications

DNA demethylation and histone deacetylation inhibition co‐operate to re‐express estrogen receptor beta and induce apoptosis in prostate cancer cell‐lines

DNA demethylation and histone deacetylation inhibition co‐operate to re‐express estrogen receptor beta and induce apoptosis in prostate cancer cell‐lines

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

Androgen receptor involvement in the progression of prostate cancer.

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